Rapamycin / Everolimus in 1 year of Cancer Therapy

There is a clinical trial is about to conclude in 2022 (EVEREST).

This study is on 1545 kidney cancer patients who’ve undergone surgery to remove their tumor.

Purpose The goal of the study is to compare how long you live without return of the tumor and how long you live in patients with renal cell cancer randomly (like the flip of a coin) assigned to 54 weeks of everolimus versus 54 weeks of placebo (an inactive drug) after complete or partial removal of your kidney by surgery. The study will also compare the amount and type of side effects between the two study arms.

Dosing: 1 yrs of daily 2.5-10mg Everolimus use. Then follow them for 10 yrs.

It’ll be interesting to see if non-cancer mortality will drop after 1 yr of intense Evorolimus.

Upcoming conference paper: https://meetings.asco.org/abstracts-presentations/207883

Background info:

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10mg/day, trough levels 15 ng/ml, lots of dose reductions and dose limiting toxicities. 40% of participants quit the study after starting!

Any insight on why Everolimus being used?

How do we think about dose scaling in prevention vs curation?

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It was originally approved as a cancer drug, I believe, and thats what its used for most predominantly I think.

OK, I was wondering, with other mTOR inhibitors out there, why specifically Everolimus.

The only rapamycin like drugs are everolimus and temsirolimus. The second is injection and rapamycin has had a ton of research already.

And everolimus has just gone off patent so will be cheap.

Everolimus’ half life is 28 hours compared to 62 hours of sirolimus. Everolimus can be dosed more frequently. It also has higher bioavailability than sirolimus.

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Just to follow up on this thread now that the results have been published.

To quote the conclusion below (I’ve expanded some abbreviations to speed up reading):

Conclusions: Adjuvant Everolimus improved Risk Free Survival in Renal Cell Carcinoma patients after nephrectomy, but the nominal significance level was narrowly missed. The Risk Free Survival improvement was seen despite a high rate of early treatment discontinuation. A 21% improvement in Risk Free Survival with Everolimus was observed in patients with very high-risk disease, a group for whom adjuvant therapy may be most relevant.

Also potentially worth quoting this section of the results:

Median Risk Free Survival was not reached; the 6-year Risk Free Survival estimate was 64% for Everolimus and 61% for Placebo. Risk Free Survval improvement with Everolimus vs. Placebo was observed in the very high-risk group (HR 0.79, 95% 0.65-0.97; P1-sided= 0.011) but not in the intermediate high-risk group (HR 0.99, 95% CI 0.73-1.35, P1-sided= 0.48) (P for interaction = 0.22). With 290 deaths, Overall Survival was similar between arms (HR 0.90, 95% CI, 0.71 – 1.13; P1-sided= 0.178).

My initial interpretation is that it’s a disappointing result.

Any other takes on this? @MAC @RapAdmin

One thought that does occur to me, is that we know immune suppression occurs with chronic doses of rapamycin. In this study they were using 10mg of Everolimus daily, split morning and evening.

Would it not make sense to pulse the dose (as is being done for longevity) to give their immune system a better chance to suppress future cancer? Afaik we all rely on our immune systems to suppress cancer all the time. Also, presumably the compliance rate would be higher?

To quote the studies compliance rate:

Fewer patients completed all 54 weeks of study treatment in the Everolimus group (45% v 69%)

I interpret that to mean 45% of the Everolimus group completed all 54 weeks, compared to 69% of the placebo group?

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Another recent rapamycin for Cancer clinical trial (small, phase 1):

Phase I Trial of Encapsulated Rapamycin in Prostate Cancer Patients Under Active Surveillance to Prevent Progression.

in a 3+3 study with three eRapa dosing cohorts (cohort 1: 0.5mg/week; cohort 2: 1.0 mg/week; and cohort 3: 0.5mg/day). Patients were treated for three months and followed for an additional three months to assess safety, pharmacokinetics, quality of life (QoL), immune response, and disease progression. Fourteen patients (cohort 1: n=3; cohort 2: n=3; cohort 3: n=8) were enrolled.

Daily dosing increased central memory cell populations and exhaustion markers. No disease progression was observed. In conclusion, treatment with eRapa was safe and well-tolerated. Daily dosing produced higher frequencies of lower-grade toxicities and transient worsening of QoL, while weekly dosing impacted immune response. Future studies will verify clinical benefit and long-term tolerability.

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